Saturday 25 June 2016

Advice on MGMT unmethylated tumor

Hi,

My father (67 years) was recently diagnosed with GBM in the cerebellum after a sub-total resection. The neurosurgeon said they were able to remove almost all of the tumor mass except for some minor residue.

There were two tumors, one in the middle of the cerebellum (vermis area) and one in the left hemisphere.

The result from the histopathology says:
* High staining of Ki67 marker.
* EGFR positive staining (but doesn't say how much nor whether EGFRvIII mutated or not)
* GFAP positive staining
* Vimentin positive staining
* Mainly cytoplasmic staining of MAP II.
* No staining of IDH1 R132H mutation.
* Only few cells show staining of p53 and NSE.
* No loss of 1p36 or 19q13.
* MGMT unmethylated (9% methylation as measured with pyro sequencing)

Father has just finished 6 weeks of radio+TMZ therapy and we're scheduled to meet the oncologist on Thursday to plan the next step. I recon she will order the standard 5/23 schedule TMZ chemotherapy per the Stupp protocol.

I have tried to read up on GBM and the treatment options available. However if I understand correctly, my father's unmethylated MGMT means the 5/23 TMZ schedule is likely not effective, but maybe a metronomic TMZ schedule would be.

I have put together a cocktail of supplements:
* Curcumin (Longvida) 1000 mg/day
* Zinc 30 mg/day
* Vitamin D3 5000 IU/day
* Silibinin 800 mg/day
* Berberine 1000 mg/day
* Garlic (AGE extract) 600 mg/day
* Lycopene 20 mg/day
* Selenium (as L-selenomethionine) 200 mcg/day

I'm also looking at adding PSK/PSP as well as Pterostilbene, but haven't yet found a good supplier that delivers to Sweden.

I'm thankful to any input or advice you can give me on how to proceed.

A few questions/thoughts:

1. Would you add or remove anything from the supplement cocktail, or change the dosage?
I read that some supplements could have both negative or positive effect depending on the dosage, i.e. Quercetin. Is there a list somewhere on known/suspected supplements to avoid?

2. My father is reluctant to do anything outside of the doctor's recommendation, so I have to try to keep the supplement cocktail as simple as possible. If I understand correctly curcumin and vitamin D are considered to be two of the most promising supplements. If I have to prioritize, which of the supplements should I keep (or exchange for something else)?

3. I've noticed that many of the supplement cocktails contain three different mushrooms - Reishi, Maitake, Corioulus versicolor. Are the mushrooms basically the same (i.e. source of PSK/PSP) or do they contain completely different agents?

4. When meeting the oncologist on Thursday, should I press for some alternative to the 5/23 TMZ schedule? I.e. addition of Keppra or some other MGMT "sensitizing" drugs or should I try to press for a metronomic TMZ schedule (or both)?

5. Should I try to press for additional meds (i.e Celebrex or others) when meeting the onc? Which ones would be most important?

6. Does the pathology report give any additional useful information to help treat this or meds that I should press for/supplements to add? I'm not able to make much out of it except for the MGMT status.

7. Should I ask for any additional (selective) gene testing done on the tumor sample? If I understand the pathological report correctly, the sample is a paraffin fixed type (not frozen) so that makes it inelligible for immunovaccine samples.

8. Anything else I should think of or that you would do/recommend? As we live in Sweden, the possibility of entering trials may be limited, but I'll nevertheless ask the onc about Optune etc.

Thanks,
Peter

8 comments:

  1. Peter,
    You've clearly done a lot of homework. I have only a few suggestions for your consideration.
    If your father doesn't like pills, you might be able to supplement the selenium, lycopene, and maybe garlic with dietary sources:
    http://www.whfoods.com/genpage.php?tname=btnews&dbid=18
    http://www.pcrm.org/health/cancer-resources/diet-cancer/nutrition/how-lycopene-helps-protect-against-cancer

    And mushrooms go well with spaghetti sauce!
    You might get your father and the oncologist to agree to some things that may do double-duty for other problems.
    E.g., the keppra is a great idea and might be good as seizure prophylaxis.
    Maybe he has insomnia, and melatonin might help that.
    Possibly he has arthritis, and aspirin/NSAID/celebrex might be of use.
    If he takes one of those you might then get him to also take cimetidine/omeprazole/lansoprazole.
    Possibly he's depressed, and might benefit from amitriptyline.
    Possibly he has high cholesterol and a statin might be introduced.

    I'm pretty much agnostic or inadequately educated as yet to answer your other questions. I'm sure you'll get more input here, though.

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  2. Peter - Please make sure that your father is not on blood-thinner (Coumadin or Warfarin) before he takes Curcumin (Longvida), Berberine, Selenium, Reishi, or Maitake as they all have blood-thinning properties.

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  3. From the pathology report, EGFR-mutation means a drug called ABT-414 could be a good option. It is available in clinical trials.
    https://clinicaltrials.gov/ct2/show/study/NCT02343406
    (sites in Germany)

    One gene that should be tested is BRAF, there is a trial in Sweden. You could ask for the testing of many genes. If there are lots of mutations overall, it would bode well for immunotherapy drugs.
    https://clinicaltrials.gov/ct2/results?term=glioma&recr=Open&cntry1=EU%3ASE

    There are clinics in Germany, western part, can be expensive but could make vaccines:
    http://www.immune-therapy.net/en/praxisgemeinschaft/aerzte.php

    I have heard these exist in Sweden. You should ask about the ones using T-cell therapy or dendritic cell therapy.

    Since the tumor was preserved in formalin, a tumor-based vaccine is not possible it is the most effetive approach. They can make an artificial tumor vaccine from the mutations etc.

    The metronomic strategy works for some cancers, for gliomas it can be helpful but not exciting overall. If they are willing, it could be tried with immunotherapy drugs in trials or by compassionate use. It may reduce repressive immune cells.

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  4. Hi Peter, welcome to our group.

    1) Glad you were able to get the Longvida in Sweden. Many people are taking 2000 mg of Longvida per day. It was developed at University of California, Los Angles, as an Alzheimers treatment. More useful info can be found here:
    http://alzheimer.neurology.ucla.edu/Curcumin.html

    According to one clinical study, zinc could increase the number of CD8+ T-cells (which can kill tumor cells directly) in patients with low baseline CD8+ T-cell counts, but reduce the numbers in patients with normal or high baseline levels. Therefore we can't say unconditionally that zinc will be helpful.

    http://www.ncbi.nlm.nih.gov/pubmed/3495300

    (I'm unfortunately unable to download the full study as it's too old)

    Many people are taking 10,000 IU of vitamin D3 daily. Ideally you'd have a blood test to determine baseline levels of 25-hydroxycholecalciferol to see where his levels are at baseline.

    https://en.wikipedia.org/wiki/Calcifediol

    There are a few scattered articles showing a tumor-promoting effect of this or that supplement. I imagine that most studies showing this don't see publication, as that outcome isn't as exciting as something that slows tumor growth. In preclinical glioma models I've seen a single study with quercetin, and a study with hyperbaric oxygen alone leading to increased tumor growth rate. However, hyperbaric oxygen combined with radiation is beneficial both in animal models and human trials. Vitamin C interfered with the effects of radiation in another study. In mouse models of other types of cancers, THC injection increased tumor growth rates through immunosuppressive effects. A lot of these effects seen in mice are likely dose dependent. Also note that these same therapies can slow tumor growth when a different model is used.
    References for these comments as follows:
    http://www.ncbi.nlm.nih.gov/pubmed/24252772
    http://www.ncbi.nlm.nih.gov/pubmed/26170997
    http://www.ncbi.nlm.nih.gov/pubmed/25566497
    http://www.jimmunol.org/content/165/1/373.full

    2. I keep a list of my own top 10 favorite supplements in folder 0 of the Brain Tumor Library. I will add you if I haven't already.

    3. The mycelia of Corioulus versicolor (aka Trametes versicolor) is the source of both PSK and PSP. These product come from two different strains of the fungus. Maitake and reishi are not a source of PSK. These would all likely work in somewhat different ways. There is some evidence that more than one fungal/mushroom product could increase the benefit, for example a study that showed a combination of maitake and shiitake was more potent than either alone:
    http://www.ncbi.nlm.nih.gov/pubmed/25332990

    4. The one study that showed a metronomic TMZ schedule might be superior to a standard schedule for GBM patients with MGMT-unmethyulated tumors was a retrospective study that showed patients with EGFR-overexpressing tumors benefitted especialy from a higher does metronomic schedule.
    http://www.ncbi.nlm.nih.gov/pubmed/25739547
    Two caveats about this study are that there was no information given about why some patients were given this schedule rather than the standard schedule, so selection bias cannot be ruled out. Also, this study used a higher dose metronomic schedule (75 mg/kg) rather than the more common 50mg/kg. This would be expected to be especially hard on lymphocytes over the long term, and I wouldn't recommmend combining metronomic schedules with immunotherapy.

    Unless your father has a very open-minded oncologist, there's little chance they'll be willing to stray from the standard schedule. In this case you're better off continuing with agents like Keppra (the most common anti-seizure agent for GBM) that have shown MGMT-inhibiting abilities in preclinical studies. In a Korean study, patients with GBM who were on Keppra for at least 3 months during monthly TMZ cycles had an unexpectedly long median survival.






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    Replies
    1. [continued]
      5. There is some evidence that chloroquine might be more effective in tumors with EGFR overexpression, for example:
      http://www.ncbi.nlm.nih.gov/pubmed/23891088
      Many people are including 250 mg of chloroquine phosphate daily in their cocktails.

      6. The most important info in the pathology report was the MGMT methylation result and the EGFR positivity, although it would have been useful to know the degree of EGFR overexpression and the presence or absence of EGFRvIII.

      7. The most commonly mutated genes in adult GBM are EGFR, PTEN and TP53. It's unlikely that TP53 is mutated given that p53 protein was expressed in only a few cells. EGFR is the most important of these as there are clinical trials underway that target EGFR, as David mentioned. Also mentioned above was the fact that vaccines can be made by analyzing paraffin-embedded tumor tissue and developing a peptide cocktail based on that information. This is done at several clinics in Germany outside of clinical trials.

      8. The following trial for newly diagnosed GBM is recruiting in Sweden. Your father is probably now ineligible since he's already completed radiochemotherapy, but it might be worth talking to these investigators to see what else in the way of immunotherapy might be available there.

      Good luck!

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    2. I forgot to paste the link to the trial in Sweden:

      https://clinicaltrials.gov/ct2/show/NCT02799238

      Delete
    3. Correction to my comment, point 4: I meant 75 and 50 mg/m2 not per kilogram.

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  5. Thanks everyone for the suggestions and comments!

    My father and I met the oncologist on Thursday, but as I kind of expected, the answers were basically "no to everything".

    They will not deviate from the standard protocol by any measure, meaning no additional gene testing and no additional meds such as Keppra. I got the feeling that there wasn't really anything to discuss.

    Father will start the 5/23 schedule of TMZ this Monday.

    I also asked when follow-up MRI is scheduled and apparently they only do that after two rounds of the 5/23 TMZ schedule. They said it's too early yet, being only one month since completion of radiotherapy+low dose TMZ?

    So that's the status right now. Should I try to procure Keppra (and possibly Chloroquine) some other way or is there any supplement that could provide the same benefit? Or just skip it?

    I found this article on Ashwagandha, but it seems highly theoretical and only tested in vitro? Also the dosage seems to be 2 uM which I have no idea if it's attainable in vivo?
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380174/

    Regarding supplements, at the moment we're trying the following:

    * Vitamin D3 10000 IU daily (2x5000 IU)
    * Curcumin (Longvida) 2100 mg daily (6x350 mg)
    * Garlic (AGE extract) 600 mg daily (1x600 mg)

    When I'm able to find a mushroom supplier delivering to Sweden I'll add that as well.

    I dropped Zinc as it's effect could be dubious.

    After reading this article on Lycopene, Selenium and EGCG having adverse effects in prostate cancer patients I dropped lycopene and selenium for the time being:
    http://www.ncbi.nlm.nih.gov/pubmed/25893930
    What do you think of this report?

    I also read a report that vitamin D could increase proliferation in certain glioma cell lines (in vitro), so I'm feeling a bit unsure of this supplement right now. What do you think?
    http://clincancerres.aacrjournals.org/content/11/15/5370.long

    I've cut down the supplements to only those that most people seem to be adding to their cocktails until I feel more confident that I'm not doing unintentional harm. Maybe garlic being the exception (but what could possibly be bad with garlic :)

    Articles on Berberine seem pretty scarce, and also not many on Silibinin either?

    Any suggestions and advice is always appreciated!

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